Use of DDX3X inhibitors for the treatment of pneumovirus infections

Abstract

The invention relates to a DDX3X inhibitor for use in the treatment of pneumovirus infection in a mammal, wherein the DDX3X inhibitor may be a compound of Formula (I) wherein y, Z, R 1 , X, L, R a and R b are as defined herein. The invention also relates to compounds of Formula (I).

The invention claimed is: 
     
       1. A method of treating pneumovirus infection in a subject, wherein the method comprises administration to the subject of an effective amount of a DDX3X inhibitor, wherein the DDX3X inhibitor is a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 y is 0, 1, or 2; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkyl, substituted or unsubstituted C 1-3  acyl, substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, substituted or unsubstituted C 1-3  alkylsulfoxide, substituted or unsubstituted C 1-3  alkylsulfonyl, halo, nitro, and cyano; 
 each X is independently O or S; 
 
       and wherein 
       i) L is a bond;
 R 1  is H; and 
 either 
 a) R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and
 R b  is selected from:
 substituted or unsubstituted C 1-10  alkyl, substituted or unsubstituted C 4-8  cycloalkyl, and 
 phenyl or 6-membered heteroaryl, each of which may be optionally substituted with up to 2 substituents Z, 
 
 
 or 
 b) R a  and R b , together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclyl ring; 
 
       or 
       ii) L is selected from: 
       
         
           
           
               
               
           
         
         where n is 0, 1, 2, 3 or 4, and the wavy lines indicate the points of attachment to the rest of the molecule; 
         each R 1  is H; 
         each R 2  is a bond or is independently selected from substituted or unsubstituted C 1-3  alkyl; 
         each R 3  is selected from substituted or unsubstituted C 1-6  alkyl; 
         R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and 
         R b  is phenyl which may be optionally substituted with up to 2 substituents Z; 
       
       or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
       2. The method of  claim 1 , wherein the DDX3X inhibitor is a human DDX3X inhibitor, a bovine DDX3X inhibitor, an ovine DDX3X inhibitor, and/or a caprine DDX3X inhibitor. 
     
     
       3. The method of  claim 1 , wherein
 y is 1; 
 each Z is independently selected from methyl, acetyl, methoxy, methylthio, methylsulfoxide, methylsulfonyl, bromo, nitro, cyano, chloro and substituted C 1 alkyl; 
 each X is independently O or S; 
 
       and wherein 
       i) L is a bond;
 R a  is H; and 
 R b  is selected from:
 2-methylcyclohexyl, n-octanyl, 
 phenyl substituted with one substituent Z, 
 pyridinyl, and 
 pyrimidinyl; 
 
 
       or 
       ii) L is selected from: 
       
         
           
           
               
               
           
         
         where n is 3, and the wavy lines indicate the points of attachment to the rest of the molecule; 
         R a  is H; and 
         R b  is phenyl substituted with one substituent Z. 
       
     
     
       4. The method of  claim 1 , wherein the DDX3X inhibitor is a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein either
 a) R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and
 R b  is selected from:
 substituted or unsubstituted C 1-10  alkyl, substituted or unsubstituted C 4-8  cycloalkyl, and 
 phenyl or 6-membered heteroaryl, each of which may be optionally substituted with up to 2 substituents Z, 
 
 
 or 
 b) R a  and R b , together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclyl ring; 
 
       or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
       5. The method of  claim 4 , wherein R a  is H, R b  is selected from:
 phenyl substituted with 1 substituent Z, 
 pyridinyl and 
 pyrimidinyl; 
 
       and at least one Z is a meta or para substituent selected from methoxy, methylthio, cyano, nitro, bromo, chloro and CF 3 . 
     
     
       6. The method of  claim 1  wherein
 y is 0, 1, or 2; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkyl, substituted or unsubstituted C 1-3  acyl, substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, substituted or unsubstituted C 1-3  alkylsulfoxide, substituted or unsubstituted C 1-3  alkylsulfonyl, halo, nitro, and cyano; 
 each X is O; 
 
       and wherein
 L is a bond; 
 R 1  is H; and 
 either 
 a) R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and
 R b  is selected from:
 substituted or unsubstituted C 1-10  alkyl, substituted or unsubstituted C 4-8  cycloalkyl, and 
 phenyl or 6-membered heteroaryl, each of which may be optionally substituted with up to 2 substituents Z, 
 
 
 or 
 b) R a  and R b , together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclyl ring; 
 
       or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
       7. The method of  claim 1  wherein
 y is 0, 1, or 2; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkyl, substituted or unsubstituted C 1-3  acyl, substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, substituted or unsubstituted C 1-3  alkylsulfoxide, substituted or unsubstituted C 1-3  alkylsulfonyl, halo, nitro, and cyano; 
 each X is O; 
 
       and wherein
 L is a bond; 
 R 1  is H; and 
 either 
 a) R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and
 R b  is selected from:
 phenyl or 6-membered heteroaryl, each of which may be optionally substituted with up to 2 substituents Z, 
 
 
 or 
 b) R a  and R b , together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclyl ring; 
 
       or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
       8. The method of  claim 1  wherein
 y is 0, 1, or 2; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkyl, substituted or unsubstituted C 1-3  acyl, substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, substituted or unsubstituted C 1-3  alkylsulfoxide, substituted or unsubstituted C 1-3  alkylsulfonyl, halo, nitro, and cyano; 
 each X is O; 
 
       and wherein
 L is a bond; 
 R 1  is H; 
 R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and 
 R b  is selected from:
 phenyl or 6-membered heteroaryl, each of which may be optionally substituted with up to 2 substituents Z; 
 
 
       or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
       9. The method of  claim 1  wherein
 y is 0, 1, or 2; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkyl, substituted or unsubstituted C 1-3  acyl, substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, substituted or unsubstituted C 1-3  alkylsulfoxide, substituted or unsubstituted C 1-3  alkylsulfonyl, halo, nitro, and cyano; 
 each X is O; 
 
       and wherein
 L is a bond; 
 R 1  is H; 
 R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and 
 R b  is phenyl which may be optionally substituted with up to 2 substituents Z; 
 
       or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
       10. The method of  claim 1  wherein
 y is 1 or 2; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, and cyano; 
 each X is O; 
 
       and wherein
 L is a bond; 
 R 1  is H; 
 R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and 
 R b  is phenyl which may be optionally substituted with up to 2 substituents Z; 
 
       or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
       11. The method of  claim 1  wherein
 y is 1; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, and cyano; 
 each X is O; 
 
       and wherein
 L is a bond; 
 R 1  is H; 
 R a  is H, and 
 R b  is phenyl substituted with 1 substituent Z; 
 
       or a tautomer or a pharmaceutically acceptable salt thereof. 
     
     
       12. The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       tautomers and pharmaceutically acceptable salts thereof. 
     
     
       13. The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       tautomers and pharmaceutically acceptable salts thereof. 
     
     
       14. The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       tautomers and pharmaceutically acceptable salts thereof. 
     
     
       15. The method of  claim 1 , wherein the subject is a mammal selected from humans, cattle, sheep and goats. 
     
     
       16. A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 y is 0, 1, or 2; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkyl, substituted or unsubstituted C 1-3  acyl, substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, substituted or unsubstituted C 1-3  alkylsulfoxide, substituted or unsubstituted C 1-3  alkylsulfonyl, halo, nitro, and cyano; 
 each X is independently O or S; 
 
       and wherein 
       i) L is a bond;
 each R 1  is H; and 
 either 
 a) R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and
 R b  is selected from:
 substituted or unsubstituted C 1-10  alkyl, substituted or unsubstituted C 4-8  cycloalkyl, and 
 phenyl or 6-membered heteroaryl, each of which may be optionally substituted with up to 2 substituents Z, 
 
 
 or 
 b) R a  and R b , together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclyl ring; 
 
       or 
       ii) L is selected from: 
       
         
           
           
               
               
           
         
         where n is 0, 1, 2, 3 or 4, and the wavy lines indicate the points of attachment to the rest of the molecule; 
         each R 1  is H; 
         each R 2  is a bond or is independently selected from substituted or unsubstituted C 1-3  alkyl; 
         each R 3  is selected from substituted or unsubstituted C 1-6  alkyl; 
         R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and 
         R b  is phenyl which may be optionally substituted with up to 2 substituents Z; 
       
       or a tautomer or a pharmaceutically acceptable salt thereof, provided that the compound is other than: 
       
         
           
           
               
               
           
         
       
     
     
       17. The compound according to  claim 16 , wherein
 y is 0, 1, or 2; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkyl, substituted or unsubstituted C 1-3  acyl, substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, substituted or unsubstituted C 1-3  alkylsulfoxide, substituted or unsubstituted C 1-3  alkylsulfonyl, halo, nitro, and cyano; 
 each X is O; 
 
       and wherein
 L is a bond; 
 each R 1  is H; and 
 either 
 a) R a  is selected from H and substituted or unsubstituted C 1-3  alkyl, and
 R b  is selected from:
 substituted or unsubstituted C 1-10  alkyl, substituted or unsubstituted C 4-8  cycloalkyl, and 
 phenyl or 6-membered heteroaryl, each of which may be optionally substituted with up to 2 substituents Z, 
 
 
 or 
 b) R a  and R b , together with the nitrogen atom to which they are attached, form a 5- or 6-membered substituted or unsubstituted heterocyclyl ring; 
 
       or a tautomer or a pharmaceutically acceptable salt thereof, provided that the compound is other than: 
       
         
           
           
               
               
           
         
       
     
     
       18. The compound according to  claim 16 , wherein
 y is 0, 1, or 2; 
 each Z is independently selected from substituted or unsubstituted C 1-3  alkyl, substituted or unsubstituted C 1-3  acyl, substituted or unsubstituted C 1-3  alkoxy, substituted or unsubstituted C 1-3  alkylthio, substituted or unsubstituted C 1-3  alkylsulfoxide, substituted or unsubstituted C 1-3  alkylsulfonyl, halo, nitro, and cyano; 
 each X is O; 
 
       and wherein
 L is a bond; 
 each R 1  is H; 
 R a  is selected from H and substituted or unsubstituted C 1-3  alkyl; and 
 R b  is phenyl which may be optionally substituted with up to 2 substituents Z; 
 
       or a tautomer or a pharmaceutically acceptable salt thereof, provided that the compound is other than: 
       
         
           
           
               
               
           
         
       
     
     
       19. The compound of  claim 16 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       tautomers and pharmaceutically acceptable salts thereof. 
     
     
       20. The compound of  claim 16 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       tautomers and pharmaceutically acceptable salts thereof. 
     
     
       21. The compound of  claim 16 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       tautomers and pharmaceutically acceptable salts thereof. 
     
     
       22. A pharmaceutical composition comprising the compound of  claim 16  and a pharmaceutically-acceptable excipient. 
     
     
       23. A method of identifying an agent which modulates pneumovirus replication comprising contacting an agent with (a) an RNA construct comprising the sequence of nucleotides 392-511 of the pneumovirus M2 transcript and (b) a protein comprising DDX3X, and determining whether the agent modulates the interaction between the construct and DDX3X. 
     
     
       24. The method of  claim 23 , wherein the pneumovirus is a human RSV (hRSV). 
     
     
       25. The method of  claim 23 , wherein the pneumovirus is a bovine RSV (bRSV).